Obesity and its co-morbidities are global public health problems. The role of the central nervous system in energy balance is being intensively investigated. Recently fatty acid metabolism has been implicated in the central nervous system regulation of food intake and energy balance. Long chain fatty acyl CoAs (LCFA:CoAs) and malonyl CoA have both been proposed to act as signals of nutrient availability in lipid-sensing areas of the brain. The lipid-sensing neurons that monitor this signal and the mechanism by which it is integrated it into the regulation of energy balance are unknown. The central aim of this proposal is to identify the relevant lipid signal and neuronal subgroups that monitor its concentration to modulate energy balance. Using a Cre/loxP DNA recombination, fatty acid metabolism will be genetically perturbed throughout the central nervous system and in specific hypothalamic nuclei known to be involved energy balance. Carnitine palmitoyl transferase-1 and a cytosolic malonyl CoA decarboxylase will be over expressed to decrease hypothalamic LCFA:CoAs and malonyl CoA respectively. If these molecules are signals of nutrient availability, reducing their concentration in the central nervous system will mimic nutrient deficiency and stimulate increased food intake and decreased energy expenditure. This approach will identify the neuronal groups that sense lipids and the nature of the lipid signal being monitored. It will position this lipid-sensing pathway in the wiring diagram of body weight regulation and potentially provide new therapeutic targets for the treatment of obesity and its comorbidities. This proposal is also designed to facilitate the training and development of the applicant to become a skilled, independent investigator in the areas of disordered energy balance, obesity and diabetes.